Chediak-Higashi syndrome is an inherited disease of man and several animal species characterized by impaired chemotactic and bactericidal activity of polymorphonuclear leukocytes (PMN) and by frequent development of lymphoma-like disease. During the tenure of grant CA-18564 we have established that the PMN dysfunctions are associated with impaired microtubule assembly and that drugs that share in common the ability to elevate cyclic GMP correct the microtubule defect. The same drugs, particularly carbamylcholine and ascorbic acid, normalize Chediak-Higashi PMN function both in vitro and in vivo and provide marked improvement in the course of the disease in patients. It is not yet known if the onset of malignancy can also be prevented. Although the microtubule assembly defect is basic to the functional abnormalities of Chediak-Higashi leukocytes, we now have evidence that an abnormality of membrane lipid composition that is common to all cells may be the underlying lesion. Detailed investigation of this unifying concept is planned. We will also extend our evidence for abnormal accumulation of taurine in Chediak-Higashi cells and reexamine other evidence for accelerated oxidative metabolism in Chediak-Higashi PMN. Boxer and coworkers have suggested that increased cyclic AMP is the immediate cause of microtubule inhibition in Chediak-Higashi cells. We find however that cyclic AMP increases as a consequence, not a cause, of microtubule disassembly. These data indicate that adenylate cyclase may be regulated in part via an intact system of cytoplasmic microtubules. Experiments to test this novel hypothesis are described here. While our studies have emphasized a role for cyclic GMP in microtubule assembly in vivo, other investigators have proposed that cyclic AMP promotes microtubule assembly. This apparent contradiction may now be partially resolved. We describe here evidence based on cultured fibroblasts that adenosine, not cyclic AMP, may be the metabolite that causes flattening of transformed cells and prevents colchicine-induced rounding of normal cells. The latter phenomenon is not associated with microtubule stabilization. Further analysis of the action of adenosine is planned and will hopefully provide new insight into the phenomenon of 'reverse transformation'.